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Impact Journals, Oncotarget, 18(5), p. 8803-8815, 2014

DOI: 10.18632/oncotarget.2492

Impact Journals, Oncotarget, 4(6), p. 2385-2396, 2014

DOI: 10.18632/oncotarget.2960

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POU2F1 activity regulates HOXD10 and HOXD11 promoting a proliferative and invasive phenotype in Head and Neck cancer

Journal article published in 2014 by Daniel J. Sharpe, Katy S. Orr, Michael Moran ORCID, Sharon J. White, Stephen McQuaid, Terence R. Lappin, Alexander Thompson, Jacqueline A. James
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

The anti-leukemic activity of sodium dichloroacetate in p53 mutated/ null cells is mediated by a p53-independent ILF3/p21 pathway This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti-leukemic activity in p53 wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53 mutated B-CLL cells and in p53 mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53 wild-type and p53 mutated B-CLL patient cell cultures, as well as in p53 mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53 null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53 mutated leukemic cells, by acting through the induction of a p53-independent pathway.